Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients G´erald Simonneau, Nazzareno Gali`e, Pavel Jansa, Gisela Martina Bohns Meyer, Hikmet Al-Hiti, Andjela Kusic-Pajic, Jean-Christophe Lemari´e, Marius M. Hoeper, Lewis J. Rubin PII: DOI: Reference:
S0167-5273(14)00039-4 doi: 10.1016/j.ijcard.2013.12.179 IJCA 17397
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
29 May 2013 17 October 2013 31 December 2013
Please cite this article as: Simonneau G´erald, Gali`e Nazzareno, Jansa Pavel, Meyer Gisela Martina Bohns, Al-Hiti Hikmet, Kusic-Pajic Andjela, Lemari´e Jean-Christophe, Hoeper Marius M., Rubin Lewis J., Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients, International Journal of Cardiology (2014), doi: 10.1016/j.ijcard.2013.12.179
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ACCEPTED MANUSCRIPT Title page
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Long-term results from the EARLY study of bosentan in WHO functional class II
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pulmonary arterial hypertension patients
Gérald Simonneau1; Nazzareno Galiè2; Pavel Jansa3; Gisela Martina Bohns Meyer4; Hikmet Al-
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Hiti5; Andjela Kusic-Pajic6; Jean-Christophe Lemarié7; Marius M Hoeper, MD8; Lewis J Rubin9
Service de Pneumologie, Hôpital Universitaire de Bicêtre, Université Paris-Sud, Le Kremlin
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Bicêtre, France. This author takes responsibility for all aspects of the reliability and freedom
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from bias of the data presented and their discussed interpretation. Institute of Cardiology, University of Bologna, Bologna, Italy. This author takes
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responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. Charles University, 1st Faculty of Medicine, 2nd Medical Department, Clinical Department of
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Cardiology and Angiology, Prague, Czech Republic. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 4
Complexo Hospitalar Sta Casa de Porto Alegre, Porto Alegre, Brazil. This author takes
responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 5
Institute of Clinical and Experimental Medicine-IKEM, Department of Cardiology, Prague,
Czech Republic. This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
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Clinical Development, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. This author takes
responsibility for all aspects of the reliability and freedom from bias of the data presented
Effi-Stat, Paris, France. This author takes responsibility for all aspects of the reliability and
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and their discussed interpretation.
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freedom from bias of the data presented and their discussed interpretation. Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany. This
presented and their discussed interpretation.
Division of Pulmonary & Critical Care Medicine, University of California, San Diego, CA, USA.
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author takes responsibility for all aspects of the reliability and freedom from bias of the data
This author takes responsibility for all aspects of the reliability and freedom from bias of the
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data presented and their discussed interpretation.
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Address for correspondence: Gérald Simonneau Hôpital de Bicêtre
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78, rue du Général Leclerc
94270 Le Kremlin-Bicêtre, Paris, France Tel: +33 1 45 21 79 62 Fax: +33 1 45 21 79 71 E-mail:
[email protected]
Financial support: The EARLY study was funded by Actelion Pharmaceuticals Ltd.
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ACCEPTED MANUSCRIPT Conflict of interest Gérald Simonneau has served as a consultant for Actelion Pharmaceuticals Ltd, GlaxoSmithKline, Eli Lilly & Co, Novartis, Pfizer and United Therapeutics and has received
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speaker fees from Actelion Pharmaceuticals Ltd, GlaxoSmithKline & Co, Eli Lilly and Pfizer.
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Nazzareno Galiè has acted as a consultant for Actelion Pharmaceuticals Ltd, Bayer HealthCare, Eli Lilly & Co GlaxoSmithKline and Pfizer.
Pavel Jansa has acted as a consultant for Actelion, Pharmaceuticals Ltd, AOP Orphan and
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United Therapeutics and lecture fees from Actelion Pharmaceuticals Ltd, Bayer HealthCare, and GlaxoSmithKline.
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Gisela Martina Bohns Meyer has received fees for lectures and/or consultations from Bayer HealthCare, and Eli Lilly & Co and GlaxoSmithKline.
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Hikmet Al-Hiti reports no conflict of interests.
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Andjela Kusic-Pajic is an employee of Actelion Pharmaceuticals Ltd. Jean-Christophe Lemarié provided statistical support on this study funded by Actelion
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Pharmaceuticals Ltd.
Marius Hoeper has received fees for Lectures and/or consultations from Actelion
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Pharmaceuticals Ltd, Bayer HealthCare, Gilead, GlaxoSmithKline, Eli Lilly & Co, LungRx, Novartis and Pfizer.
Lewis Rubin has acted as a consultant for Actelion Pharmaceuticals Ltd, Aires, Bayer HealthCare, Gilead, GlaxoSmithKline, Lung LLC, MondoBiotech, Pfizer and United Therapeutics.
Key words: Endothelin; pulmonary arterial hypertension; risk factors; survival; bosentan
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ACCEPTED MANUSCRIPT Abstract
Background: The double-blind phase of the EARLY study of bosentan remains the only randomized controlled trial of a PAH-targeted therapy in World Health Organization
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functional class (FC) II patients. We report on the efficacy, safety, disease worsening,
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survival and prognostic factors in mildly symptomatic pulmonary arterial hypertension (PAH) patients treated with bosentan in the open-label extension phase of the EARLY study.
Methods: Exploratory efficacy outcomes included 6-minute walk distance (6MWD) and WHO
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FC. Adverse events were recorded. Kaplan–Meier analysis was used to estimate time to first PAH worsening event (death, initiation of intravenous or subcutaneous prostanoids, atrial
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septostomy or lung transplantation) and survival. Cox regression analysis determined factors prognostic of survival.
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Results: Median exposure to bosentan (n=173) was 51 months. At the end of the
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bosentan-treatment assessment period, 77.8% of patients were in WHO FC I/II. Adverse events led to discontinuation of bosentan in 20.2% of patients. Aminotransferase elevations
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>3 x upper limit of normal occurred in 16.8%. Four-year PAH-event-free survival and survival were 79.5% (95% confidence intervals [95% CI] 73.4, 85.6) and 84.8% [95% CI
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79.4, 90.2], respectively. Low 6MWD, low mixed venous oxygenation, high N-terminal pro hormone of brain natriuretic peptide levels and PAH associated with connective tissue disease were associated with a higher risk of death.
Conclusions: The majority of patients exposed to long-term bosentan maintained or improved their functional class. Approximately 20% of the patients discontinued treatment because of adverse events, which were most commonly PAH worsening and elevated liver enzymes.
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ACCEPTED MANUSCRIPT 1. Introduction
Pulmonary arterial hypertension (PAH) is characterized by remodeling of the pulmonary
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vasculature [1]. Progressive vasculopathy results in an increase in pulmonary arterial
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pressure (PAP) and pulmonary vascular resistance (PVR), ultimately leading to right heart failure and death [2].
The World Health Organization functional class (WHO FC) system comprises four classes
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(I–IV), and characterizes patients with PAH by increasing functional compromise with symptoms such as dyspnea, fatigue, chest pain, and syncope initially on exertion and
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subsequently at rest. At the time of diagnosis, approximately 75% of patients are in WHO FC III/IV [3]. Functional class at the time of diagnosis as well as during follow-up is of pivotal
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prognostic importance [4]. Patients starting therapy in WHO FC I/II have a better prognosis
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than those in WHO FC III/IV [5] and patients who achieve WHO FC I/II after treatment have a better prognosis than those who remain in WHO FC III/IV [6,7]. Despite a relatively well
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preserved exercise capacity and mild symptoms, patients in WHO FC II are already hemodynamically compromised [8]. Therefore, both treating and maintaining patients in
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WHO FC II or better is a logical treatment strategy. To date, EARLY (Endothelin Antagonist tRial in miLdlY symptomatic PAH patients) remains the only prospective, randomized, placebo-controlled, clinical trial of a PAH-targeted therapy in an exclusively WHO FC II PAH patient population. This multicenter study randomized 185 patients from 21 countries to receive bosentan or placebo over a 6-month double-blind treatment period. Bosentan significantly reduced PVR in comparison with placebo (-22.6%,
p 75% patients had data
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ACCEPTED MANUSCRIPT available at this time point), in patients for whom data were available at each specific time point, were reported for 6MWD and Borg dyspnea index. Changes in WHO FC from baseline were reported at study end. The proportions of patients who improved to a lower FC or
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deteriorated to a higher FC at the end of treatment were also provided together with 95%
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confidence intervals (CI).
Safety data are presented for patients who had ≥ 1 AE and events per 100 patient-years are provided. Elevations of ALT/AST > 3 × upper limit of normal (ULN) and marked
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decreases in hemoglobin ≤ 10 g/dL during the bosentan-treatment period are described. Time to first ALT/AST elevation during the same treatment period with event rate corrected
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to account for individual exposure times was determined by Kaplan–Meier analysis. For PAH worsening and survival, Kaplan–Meier analysis (estimates reported as
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percentages and 95% CI) was used to estimate time to PAH worsening and its separate
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components. A post-hoc comparison of the patients on monotherapy at the start of the EARLY study who remained on monotherapy with those who had moved on to combination
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therapy at 4 years was performed for patients who had a) died, b) were known to be alive and c) who had been censored. Time to death was further estimated by Kaplan–Meier
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analysis according to PAH etiology, as was time to initiation of other PAH-targeted drugs (oral phosphodiesterase type 5 inhibitors and/or oral/inhaled prostanoids).
2.5.
Cox analysis on the all-randomized population
In order to determine factors prognostic of survival, Cox regression analyses were conducted on the all-randomized population which included all randomized patients, whether they received study medication or not. Univariate (significance set at p 8 × ULN) were unresolved but
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had, prior to bosentan discontinuation, been treated without tolerability issues for 3.5 years. The elevations in liver enzymes were considered by the investigator not to be related to
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bosentan treatment. At the last safety follow-up before study end her clinical condition improved and liver function tests were being conducted twice weekly.
Over the 5-year duration of the study, 29/173 (16.8%) patients experienced elevations in ALT and/or AST > 3 × ULN, with 14 patients (8.1%) having elevations > 8 × ULN. The majority of the ALT and/or AST elevations occurred by Year 1, with all 20 events actually occurring in the first 6 months, giving a crude event rate of 11.6% at Month 6. The number of additional events by Years 2, 3, 4 and 5 were 5, 2, 1 and 1 respectively. The Kaplan– Meier estimate of time to AST/ALT elevation which corrected for the shorter exposure time of bosentan for some patients provides event rates of 12.0% at Month 6 (which is the same as
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ACCEPTED MANUSCRIPT at Year 1) and 18.6% at Year 5 (Fig. 3). The Kaplan–Meier curve clearly shows that the majority of these cases occurred within the first 6 months of bosentan treatment, with few additional patients experiencing liver enzyme elevations - after 6 months.
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All but one case of elevated liver enzymes, as described above in the patient with pre-
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existing, recurrent autoimmune hepatitis, resolved after either a decrease in the bosentan dose, continued treatment, or after treatment discontinuation.
A hemoglobin concentration of ≤ 10 g/dL was found in 26 (15.0%) patients, only one of
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whom had a pre-treatment baseline value of ≤10 g/dL. No patient discontinued bosentan due to anemia, two patients required dose reduction, and transfusion was reported in six
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cases.
A total of 30 deaths occurred up to end of study in the bosentan treated-population; 21
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deaths had occurred within the 28-day period after bosentan discontinuation and nine had
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occurred more than 28 days after bosentan discontinuation. Of the patients who died during the bosentan treatment period or within 28 days after discontinuation, progression of PAH
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(four patients), pneumonia and sudden death (three patients each) were the most frequent causes of death. The treating physician judged death to be related to study medication in
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two cases (convulsions/vasculitis/worsened PAH, and antiphospholipid syndrome/sudden death/systemic lupus erythematosus).
3.2.5. PAH worsening and survival The estimated proportion of patients who remained free of PAH worsening (event-free survival) at 1, 2, 3, and 4 years were 96.5%, 90.7%, 87.8%, and 79.5%, respectively (Fig. 4A). PAH worsening events, which occurred as first events, were death (n=25) and initiation of iv or sc prostanoids (n=18). Two patients underwent lung transplantation, both of whom first received iv or sc prostanoids. Survival estimates at 1, 2, 3, and 4 years were 97.1%,
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ACCEPTED MANUSCRIPT 92.4%, 90.1%, and 84.8%, respectively (Fig. 4B). Patients with PAH-CTD had poorer survival than those with idiopathic/heritable PAH or PAH-CHD (Fig. 4C). It was estimated that after 4 years, 7.6% of patients had received iv or sc prostanoid
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therapy (Fig. 4D) and 29.6% of patients had received other PAH-targeted drugs, namely
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phosphodiesterase type 5 inhibitors (sildenafil or tadalafil) and/or oral/inhaled prostanoids (Fig. 5). At 4 years, among the 144 patients who had started bosentan as a monotherapy (i.e. excluding the 29 already on sildenafil at baseline, see Table 1), 21 were known to have
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died (15 remained on monotherapy, six had received combination therapy) and four were lost to follow-up and censored. Of the 119 patients known to be alive at 4 years, 75
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remained on monotherapy and 44 had moved to combination therapy. All four censored
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patients were on monotherapy at time of censoring.
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3.2.6. All-randomized population – prognostic factors of survival The univariate Cox analysis conducted in the all-randomized population, for which there
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were 35 deaths in this population, showed significant prognostic factors for a high risk of death were time since PAH diagnosis of up to 16 months, 6MWD ≤ 437 m, mixed venous
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oxygen saturation ≤ 68%, high levels of N-terminal pro hormone of brain natriuretic peptide (NT-proBNP) and a diagnosis of PAH-CTD (Table 3). With the exception of time since PAH diagnosis, all these factors were confirmed as significant in the multivariate analysis (Table 3).
4. Discussion
The exposure to bosentan in EARLY exceeds that of many other studies. As such, EARLY provides valuable information on the long-term safety, in particular liver safety, of bosentan in patients with PAH. The 4-year data from this study also underscore the fact that patients
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ACCEPTED MANUSCRIPT with WHO FC II PAH have a severe and often fatally progressive disease. PAH worsening occurred at a rate of approximately 5% annually and mortality, estimated at 15% over 4 years, remains substantial. An important finding of this study was the identification of a priori
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factors that portend a poor outcome in WHO FC II patients treated with monotherapy. This
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could be useful in identifying a high-risk incident population that might benefit in particular from up-front combination therapy. Lastly, the use of standard efficacy measures in EARLY can also provide some indication of the symptomatic efficacy of bosentan over the long-term
Safety
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4.1.
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but these data need to be interpreted with caution.
Information on elevations in liver enzymes was of primary importance in the EARLY
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study given the long period of bosentan exposure in this study of up to 5 years. Thus we
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report all elevations of AST and/or ALT regardless of whether they led to bosentan discontinuation. The proportion of patients with AST and/or ALT elevations (irrespective of
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whether they led to bosentan discontinuation or not) in EARLY was 16.8% (crude rate) or 18.6% by Kaplan–Meier estimate. Given that most patients were treated for at least 4 years,
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this rate is not unexpected and is similar to that of open-label bosentan studies of up to 3 years exposure [9]. Consistent with these previous findings [9] most of the increases in AST and/or ALT associated with bosentan occurred during the first 6 months of treatment. The crude rate estimate at Month 6 of 11.6% and the Kaplan–Meier estimate of 12.0% are similar to the 6-month estimate of 11.3% reported in the Tracleer® (bosentan) Summary of Product Characteristics [10]. While it is more likely that later increases in liver enzymes are associated with the disease or other background factors or concomitant medications given as patients deteriorate, bosentan-related increases cannot be excluded from occurring later on during the course of therapy. These data highlight that monthly blood tests to monitor liver enzymes should be conducted the entire time a patient is treated with bosentan. Treatment
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ACCEPTED MANUSCRIPT discontinuation, dose reduction or continued treatment coupled with regular assessment should be employed in cases of liver enzyme abnormalities. As evidenced in this study, most cases of elevated liver enzymes are resolved after deployment of one of these strategies.
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Of the 29 patients with elevated liver enzymes of > 3 × ULN, 16 discontinued
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bosentan treatment. For 13 of these patients, the elevations were asymptomatic and recorded as either an AE of abnormal liver enzymes (in 12 patients) or specified as an AE of increased ALT and AST. Three patients had elevated aminotransferases with a clinical
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presentation of hepatitis, which was recorded as the AE leading to discontinuation. In two of these cases the investigator considered the hepatitis to be drug related, however as liver
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biopsy was not performed it is not possible to confirm if this was the case. Seven patients discontinued bosentan due to worsening of their pulmonary
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hypertension, one in the double-blind phase of the study and six in the open-label phase. In
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the double-blind phase the protocol specified that patients who worsened should discontinue treatment. While in the open-label phase patients could continue bosentan treatment if
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another PAH-targeted therapy was added, combination therapy was not common clinical practice during some of the time the trial was being conducted.
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Twenty-one patients died while taking bosentan, or within 28 days after cessation, and most deaths were due to PAH or conditions that would be expected in a population of chronically ill patients. In two cases death was linked by the treating physicians to bosentan (see above).
4.2.
Estimates of PAH worsening and survival, and prognostic factors for survival
As data on PAH worsening and vital status were collected for all bosentan-treated patients, independently of treatment duration, EARLY provides the first disease worsening and survival data for a WHO FC II PAH population. At 4 years, event-free survival and
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ACCEPTED MANUSCRIPT survival were approximately 80% and 85%. These data confirm that survival has improved in the era of PAH-targeted therapy versus historical data from the pre-drug era [11]. However, a death rate of 15% over 4 years in a mildly symptomatic PAH patient population
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still shows how further research into new treatments, more effective treatment strategies,
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and understanding the disease are still required.
Data collection on vital status for all randomized patients also enabled a Cox analysis to be conducted to identify factors that were predictive of death. We identified 6MWD of 437 m
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or less, a PAH diagnosis of 16 months or less, a mixed venous oxygen saturation of 68% or less, high NT-proBNP levels, and PAH-CTD as factors prognostic of a high risk of death in
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WHO FC II patients. Such information can alert physicians to pay particular attention to patients with risk factors and employ modified treatment strategies such as more regular
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assessment or more aggressive treatment including up-front combination therapy, although
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this is not currently supported by randomized clinical trial evidence. Similar high risk factors have also been identified in other studies. In the Sildenafil Use in
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Pulmonary Hypertension (SUPER)-2 trial, Cox regression analysis showed that for patients who had a 6MWD of < 325 m at baseline in SUPER-1, deterioration in 6MWD during the first
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12 weeks of sildenafil treatment was associated with poor survival (hazard ratio 0.241). The association was weaker between change in 6MWD and survival in patients with a 6MWD ≥ 325 m at baseline [12]. High 6MWD (≥ 440 m) is also associated with a low score on The Registry to EValuate Early And Long-term pulmonary arterial hypertension disease management (REVEAL) risk score calculator [13]. Although time since diagnosis of more than 16 months was no longer predictive of better survival in the multivariate analysis, it should be noted that the multivariate analysis was underpowered compared with the univariate analysis since patients who had missing data for any the parameters included in the multivariate analysis were excluded.
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ACCEPTED MANUSCRIPT B-type natriuretic peptide (BNP) and NT-proBNP are biomarkers of heart failure and high plasma levels have consistently been reported as predictors of mortality [15–17]. NT-proBNP levels > 1,400 pg/mL and > 1,800 pg/mL, respectively, have been shown to be predictive of
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worse 3-year outcomes in patients with severe PAH [7,17] and prognostic analysis from
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REVEAL shows BNP levels > 180 pg/mL are significantly associated with death [15]. High BNP levels are part of the risk score calculator from REVEAL [13].
That the Cox regression analysis identified PAH-CTD as a high risk is congruent with the
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Kaplan–Meier survival analysis by etiology in this study and in other studies, such as the French PAH Registry [18], which showed PAH-CTD patients to have poorer survival than
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those with iPAH or PAH-CHD. REVEAL confirms a significantly lower survival rate at 1 year in
Exploratory efficacy outcomes of bosentan treatment
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4.3.
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PAH-CTD vs iPAH, 86% vs 93%; p 16
6MWD (> 437 m)
p
95% CI
(n=142†)
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Time since PAH
Hazard ratio
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(n=185) Baseline parameter
Multivariate analysis
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Univariate analyses
oxygen saturation > 68% (n=167) NT-proBNP
(10-fold
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increase) (n=158)
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0.0090*
Etiology (n=185)
0.1234
2.33
1.15–4.75
0.0192
–
–
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- CTD vs iPAH/hPAH-HIV - CTD vs iPAH /hPAH - HIV - CHD
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iPAH/hPAH-HIV
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- CHD vs
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1.81–10.09
0.0009¶
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*Global test for influence of etiology
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Multivariate analysis was conducted on patients without missing data for the variables retained (p-value < 0.1 in univariate analyses)
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Dropped from the multivariate analysis during backward selection
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Risk of a patient with an NT-proBNP level 10-fold greater than another patient who otherwise has the same characteristics
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Since (CHD vs iPAH/hPAH-HIV) was not selected by univariate analyses, etiology was reduced to CTD vs iPAH/hPAH-HIV-CHD
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†
Variables included in the univariate analyses: Time from diagnosis (≤ 16 months, > 16 months); randomization group at start of double-blind (placebo, bosentan); 6MWD (≤ median, > median); NT-proBNP (log-transformed); cardiac index (≤ median, > median); pulmonary vascular resistance (≤ median, > median); mixed venous oxygen saturation (≤ median, > median); sex (male, female); age (≤ median, > median); etiology (3 classes: iPAH/hPAH-HIV, CHD, CTD); mean blood pressure (from vital signs (≤ median, > median); monotherapy/combination therapy (sildenafil) therapy at baseline.
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CHD = congenital heart disease; CTD = connective tissue disease, HIV = human immunodeficiency virus; iPAH/hPAH = idiopathic/heritable
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pulmonary arterial hypertension; NT-proBNP = N-terminal pro hormone of brain natriuretic peptide; 6MWD = 6-minute walk distance.
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Supplementary tables
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Table S1. Number and percentage of patients exposed to bosentan over the
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course of both the double-blind and open-label extension phases of the EARLY
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study
Patients
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Year
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≥ 1 year ≥ 2 years
≥ 5 years
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36 (20.9%) 2 (1.2%)
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≥ 6 years
131 (76.2%)
106 (61.6%)
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≥ 4 years
143 (83.1%)
126 (73.3%)
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≥ 3 years
(n=172)*
*Total number of patients in the bosentan-treated population was 173 but one patient was lost to follow-up and so exposure could not be calculated. Therefore denominator for calculating bosentan exposure was 172
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Table S2. Adverse events (AE) leading to discontinuation of bosentan treatment
Patients
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AE
At least one AE leading to discontinuation
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n (%)
Event/100 patient-years
35 (20.2)
5.6
12 (6.9%)
1.9
7 (4.0%)
1.1
2 (1.2%)
0.3
2 (1.2%)
0.3
2 (1.2%)
0.3
Alanine and aspartate aminotransferases increased
1 (0.6%)
0.2
Antiphospholipid syndrome
1 (0.6%)
0.2
Autoimmune hepatitis
1 (0.6%)
0.2
1 (0.6%)
0.2
Circulatory collapse
1 (0.6%)
0.2
Convulsion
1 (0.6%)
0.2
Exertional dyspnea
1 (0.6%)
0.2
Exercise tolerance decreased
1 (0.6%)
0.2
Gastroesophageal reflux disease
1 (0.6%)
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Abnormal liver function test
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Worsening pulmonary hypertension Adverse drug reaction
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Sepsis
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Sudden death
Brain stem infarction
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ACCEPTED MANUSCRIPT 1 (0.6%)
0.2
Hepatitis*
1 (0.6%)
0.2
Hepatitis C*
1 (0.6%)
0.2
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Heart and lung transplant
1 (0.6%)
Insomnia
0.2
1 (0.6%)
0.2
1 (0.6%)
0.2
1 (0.6%)
0.2
1 (0.6%)
0.2
1 (0.6%)
0.2
1 (0.6%)
0.2
1 (0.6%)
0.2
Right ventricular failure
1 (0.6%)
0.2
Systemic lupus erythematosus
1 (0.6%)
0.2
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Toxic hepatitis
1 (0.6%)
0.2
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Localized infection Nervous system disorder
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Peripheral edema
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Shock
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Pancreatitis acute
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Vasculitis
Pancreatic carcinoma
*Hepatitis and hepatitis C were recorded as reasons for discontinuation in the same patient. The investigator considered both bosentan treatment and viral factors to be causative of hepatitis in this patient.
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